Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA, 94038, USA.
Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA, 94720, USA; QB3 Institute for Quantitative Biosciences, University of California Berkeley, Berkeley, CA, 94720, USA; Department of Chemistry, University of California Berkeley, Berkeley, CA, 94720, USA.
Curr Opin Struct Biol. 2022 Apr;73:102345. doi: 10.1016/j.sbi.2022.102345. Epub 2022 Mar 2.
Ubiquitin is a small eukaryotic protein so named for its cellular abundance and originally recognized for its role as the posttranslational modification (PTM) "tag" condemning substrates to degradation by the 26S proteasome. Since its discovery in the 1970s, protein ubiquitination has also been identified as a key regulatory feature in dozens of non-degradative cellular processes. This myriad of roles illustrates the versatility of ubiquitin as a PTM; however, understanding the cellular and molecular factors that enable discrimination between degradative versus non-degradative ubiquitination events has been a persistent challenge. Here, we discuss recent advances in uncovering how site-specificity - the exact residue that gets modified - modulates distinct protein fates and cellular outcomes with an emphasis on how ubiquitination site specificity regulates proteasomal degradation. We explore recent advances in structural biology, biophysics, and cell biology that have enabled a broader understanding of the role of ubiquitination in altering the dynamics of the target protein, including implications for the design of targeted protein degradation therapeutics.
泛素是一种小型真核蛋白，因其在细胞中的丰富性而得名，最初因其作为翻译后修饰 (PTM) “标签”的作用而被识别，该标签将底物标记为通过 26S 蛋白酶体降解。自 20 世纪 70 年代发现以来，蛋白质泛素化也被确定为数十种非降解细胞过程中的关键调节特征。这种多样性的作用说明了泛素作为 PTM 的多功能性；然而，理解使细胞能够区分降解与非降解泛素化事件的细胞和分子因素一直是一个持续的挑战。在这里，我们讨论了揭示特定残基修饰如何调节不同蛋白质命运和细胞结果的最新进展，重点讨论了泛素化位点特异性如何调节蛋白酶体降解。我们探讨了结构生物学、生物物理学和细胞生物学方面的最新进展，这些进展使人们对泛素化在改变靶蛋白动力学中的作用有了更广泛的理解，包括对靶向蛋白质降解治疗药物设计的影响。
